Modified aryldifluorophenylsilicates with improved activity and selectivity in nucleophilic fluorination of secondary substrates

Nucleophilic fluorination of secondary aliphatic substrates, especially of halides, still remains a challenge. Among the available reagents, TBAT belongs to one of the best choices due to its stability, affordable price and low toxicity. With the aim to improve its selectivity, we synthesized three analogues modified in the aryl part of the TBAT reagent with one or two electron donating methoxy groups or with one electron withdrawing trifluoromethyl group. All three reagents are air-stable compounds and their structure was confirmed by a single crystal X-ray analysis. In testing the reactivity and selectivity of the reagents with a library of secondary bromides, as well as of other selected primary and secondary substrates, we found that substitution with methoxy groups mostly improves both reactivity and selectivity compared to TBAT, while the substitution with trifluoromethyl group leads to inferior results. Difluorosilicates modified by more than two electron donating methoxy groups proved to be unstable and decomposed spontaneously to the HF2− anion. DFT calculations of tetramethylammonium analogues of the studied reagents disclosed that the substitution of the phenyl group with the methoxy substituent lowers the transitions state energy of the decomposition to a fluorosilane–fluoride complex, while the substitution with the trifluoromethyl group has an opposite effect.


Introduction
Organouorine compounds nd plentiful applications in medicinal chemistry, 1-3 agrochemistry 4 and industrial chemistry. 5Because radical or electrophilic uorination requires the use of either highly corrosive uorine gas or expensive electrophilic uorinating reagents, nucleophilic uorination still remains a basic tool for the synthesis of uorinated substances. 6,7In analogy to other halogenations, either substitution of a hydroxy group forming in situ both leaving group and uoride anion 8 or uorination of an appropriate leaving group such as sulfonate or halide group can be employed.For secondary aliphatic substrates, cheap reagents such as KF lead to preferential elimination due to its high basicity and poor solubility, secondary halides being most sensitive. 9Although it can be partially solved using crown ethers, cryptands or ionic liquids, 6,9 especially in the combination with sterically hindered alcohols, [10][11][12] these systems were not tested on secondary halides.Secondary bromide was successfully uorinated by the combination of KF, sterically hindered alcohol and complex calixcrown ether. 13,14While the problem of solubility can be solved using quaternary ammonium cations, high basicity of TBAF (1) still remains the issue, 15,16 which was partially solved by the use of sterically hindered hydrogen bond donors such as tert-butyl alcohol. 17The structure of KF-alcohol complexes was studied further both experimentally 17 and theoretically. 18nfortunately, no secondary halides were tested as substrates.
2-Bromooctane (2a) belongs to the substrates most prone to elimination and hence is oen used as a benchmark for assignment of activity and selectivity of uorinating reagents.The best results were reported to be achieved by a combination of tetrabutylammonium hydrogen diuoride in a 1 : 1 mixture with pyridine (75% substitution, 25% elimination), but no full experimental details are given. 19Second best reported yield was achieved using expensive AgF in combination with 2,2 0 -bipyridine (55%). 20Recently, 35% yield of uorination was reported using a new class of reagents, stable dihydropyrrole NHC based dihydrogen triuoride 3 (Fig. 1). 21ne of the most promising, stable and commercially available uorinating reagents, TBAT (4a), gave 2-uorooctane with only 34% selectivity and high sixfold excess of reagent was used. 22We recently found that a twofold excess of TBAT is sufficient and that tetrabutylammonium cation prone to elimination can be substituted by other quaternary cations. 23he role of the presence of electron donating or electron withdrawing substituents on the activity of the TBAT analogue has never been studied with the exception of short remark by Ma ˛kosza et al., which synthesized tetrabutylammonium tris(4chlorophenyl)diuorosilicate and tetrabutylammonium diuorotris(4-methylphenyl)silicate. 24They found that the latter reagent acts signicantly more quickly than TBAT in uorination of benzyl bromide. 25We hence wondered how the modication of the phenyl groups in TBAT (4a) with more strong electron donating or electron withdrawing groups will inuence the activity and selectivity of the reagent not only with 2-bromooctane, but also with a larger series of secondary substrates.Our choice of possible substituents was limited by the synthetic approach including organometallic reagents, thus excluding stronger electron donating, e.g.amino groups, as well as stronger electron accepting, e.g.nitro or carbonyl groups.Using DFT methods, we also decided to study how this substitution will inuence the PES (potential energy surface) of decomposition of diuorosilicates to uorosilane-uoride complexes as a rst step of larger computational studies, targeted to understand better the mechanism of uorinations with diuorosilicates.We found that modication of TBAT reagent with one or two electron donating methoxy groups (MeOTBAT, 4b, (MeO) 2 TBAT, 4c), improved the selectivity of uorination for several secondary substrates including 2-bromooctane (2a), while the substitution with the electron withdrawing triuoromethyl group led to inferior activity and selectivity (Scheme 1).

Results and discussion
New diuorosilicates 4b-4d were obtained by the reaction of the corresponding uorosilanes 6a-6c with the solution of TBAF in THF.While uorosilanes 6a, 6b containing one or two 4methoxyphenyl groups were obtained by the reaction of commercial organomagnesium reagent with diuorodiphenylsilane or triuorophenylsilane, uorosilane 6c containing 4-(triuoromethyl)phenyl group was formed using 4-(triuoromethyl)phenyllithium, which was prepared from 1bromo-4-(triuoromethyl)benzene and tert-butyllithium (Scheme 2).
Diuorosilicates 4b-4d are air stable compounds, their single crystal structures were obtained and are shown on Fig. 2. The details of crystallographic analyses are given in ESI.† The Si-F distances are quite identical for all three structures (172.6-172.7 pm for one SiF bond and 173.3-173.7 pm for the other), while the energy of the uorosilane-uoride complex probably does not depend much on the Si-F-N angle and hence this varies quite signicantly from nearly perpendicular (107.6°) for 4c to nearly linear (162.3°) for 4b.
In contrast to the previous research where high six fold excess has been employed, 22 we in an analogy to our recent paper 23 employed just two fold excess of the reagent and obtained nearly full conversion (Table 1 entry 3).On the other hand, the use of just one equivalent resulted in both inferior conversion and selectivity (Table 1 entry 4).Twofold excess of the reagents was thus used for all further uorinations and products of elimination to E/Z-oct-2-ene 7b and oct-1-ene (7a) were observed as the only side products.We also studied the role of the leaving group on the octan-2yl moiety.The substitution/elimination ratio decreased in the order: -OMs > -Br > -I > -Cl.
A small set of secondary bromides was uorinated with diuorosilicates 4 and the results are shown in Fig. 4. Fluorination of (1-bromoethyl)benzene (8) and bromocyclopentane (10) was in line with the previous results.Quite surprisingly, TBAF (1) gave the best results for uorination of bromocyclohexane (9) and all diuorosilicates 4 failed to give acceptable    results.On the other hand, secondary bromides with adjacent electron withdrawing groups (ester, ketone) gave very good yields of uorination for all diuorosilicates 4, showing that they are not optimal substrates for testing purposes.
Regarding the poor results of uorinations of bromide 9, we believe that steric hindrance can play here the major role together with high proneness to E2 elimination from the favorable cyclohexane ring conformation.
Furthermore, several primary and secondary substrates were also uorinated for comparison in good to excellent yields (Fig. 5).
Encouraged by improved selectivity of methoxy group substituted analogues of TBAT, we synthesized starting uorosilanes 6d-6g, containing even more methoxy groups.The synthesis employed similar strategy as the synthesis of uorosilane 6c, namely bromine-lithium exchange by BuLi, followed by the reaction with the corresponding uorophenylsilane or, in the case of uorosilane 6d, with tetrachlorosilane followed by uorination with CsF (Scheme 3).First purication was performed by vacuum distillation.In the case of uorosilanes 6g, 6h bearing trimethoxyphenyl groups, lower conversion was caused by steric hindrance and the distilled products were contaminated by starting uorophenylsilanes and other side-products.Fortunately, while trituration with a 7 : 1 hexane/dichloromethane mixture removed starting uorophenylsilanes, pure hexane subsequently removed other organic side-products to give pure products 6g, 6h (Scheme 4).
Unfortunately, all attempts to prepare the corresponding diuorosilicates 4e-4i in an analogy to diuorosilicates 4a-4c resulted in the formation of unstable diuorosilicates or diuorosilicate/HF 2 − mixtures, which slowly decomposed in an analogy to diuoromethyldiphenyl silicate anion, reported by us earlier, 23 to HF 2 − anion (see the spectra in ESI †) (Scheme 5).
Thus, diuorosilicate 4d probably represents the borderline stable structure.We further attempted to prevent possible elimination of HF from Bu 4 N + cation, substituting it for neopentyltrimethyl-ammonium (NpMe 3 N + ) cation and changing the solvent for toluene, but with the same outcome (see the spectrum in ESI †).The source of the proton to form HF 2 − anion from unstable diuorosilicates 6d-6h is unknown to us especially in the latter case, both starting uorosilanes and neopentyltrimethyl-ammonium uoride were dried for several days under high vacuum.This will be the aim of our further studies.

Computations
Finally, we wondered how substitution with electron donating methoxy group or electron withdrawing triuoromethyl group will inuence the geometry of aryldiuorodiphenylsilicates and how it will inuence the activation energy of their decomposition to uorosilane-uoride complexes.Recently, the mechanism of the decomposition of TBAT to uorosilane and TBAF was studied by a variety of NMR methods in THF and MeCN and found to be 72.5 kJ mol −1 at 300 K in THF and probably lower in MeCN. 26We hence started a DFT study of these compounds.This is the rst part of a larger computational study related to the mechanism of nucleophilic uorination with diuorosilicates, which is yet unknown.In more detail, it is not known whether direct transfer of uorine (and which of the two uorine atoms) to the substrate proceeds, or whether this is a two step process with rst decomposition to uorosilane and uoride, followed by uorination with naked uoride anion.For simplicity, we substituted tetrabutylammonium cation with simpler tetramethyl ammonium.While preliminary calculations were performed using Gaussian 16 program suite, 27 quantitative results were obtained with the ORCA computational program. 28Full details and discussion of the minimal geometries are given in ESI.† The computed structures of diuorosilicate 18a containing three phenyl groups, diuorosilicate 18b modied with the methoxygroup and diuorosilicate 18c with the triuoromethyl group agree well with the obtained single crystal structures, the error in the Si-F lengths not exceeding 1 pm.On the other hand, the Si-F-N angle differs signicantly from the crystal structures, because this is given mostly by crystal packing.Compared to diuorotriphenylsilicate (18a), the presence of the electrondonating methoxygroup in the aryl in 18b results in lowering of both the transition state and uorosilane-uoride complex 19b energies by about 4 kJ mol −1 , while the presence of the electron-accepting group in 18c has just the opposite effect (19c) (see Fig. 6 for the key structures and saddle point energies).
To bring some rationale to the experimental results, analysis of the computed structures shows that the presence of electrondonating methoxy group on the phenyl ring decreases the positive hyperconjugation from the Si-F bonds, resulting in smaller Mulliken charge on silicon and longer Si-F bond (−0.327 and 1.741 Å, respectively) compared to unsubstituted phenyl (−0.351 and 1.740 Å, respectively).On the other hand, the presence of electron-accepting triuoromethyl group on the ring results in higher positive hyperconjugation from the Si-F bonds, resulting in higher Mulliken charge on silicon and shorter Si-F bond (−0.602 and 1.733 Å).Correspondingly, longer Si-F bonds in the silicate imply higher nucleophilic reactivity with a soer reagent and shorter Si-F bonds lower nucleophilic reactivity and enhanced elimination due to a harder reagent.

Materials and methods
All reactions were performed under an argon atmosphere in oven dried asks using standard inert technique, unless otherwise noted.Fluorinations were performed in sealed vials. 1 H NMR spectra were recorded with Agilent 400-MR DDR2 spectrometer at working frequencies 399.94 MHz for 1 H NMR, 376.29 MHz for 19 F NMR and 100.58MHz for 13 C NMR or with JEOL-ECZL400G spectrometer at working frequencies 399.78 MHz for 1 H NMR, 376.17 MHz for 19 F NMR and 100.53MHz for 13 C NMR, in deuterated solvents.Chemical shis (d) are reported in parts per million (ppm) with reference to the residual solvent peak.Signals are described as s = singlet, d = doublet, t = triplet, m = multiplet, bsbroad singlet.

Fluorinations
General procedure.5 mL Schlenk ask was charged with uorinating reagent (2.0 equiv.),substrate (1.0 equiv., 20 mg) and CD 3 CN (0.7 mL).The ask was sealed and heated on metallic block to 85 °C for 24 h.Aer cooling, the samples were measured by 1 H NMR (16 scans, 20 s relaxation delay) and the conversions were determined from characteristic peaks of the products given below.
Results of the preliminary computations, copies of NMR spectra and xyz les of all computed structures are given in the ESI.†

Conclusions
Starting from uorosilanes 6a-6c and commercial solution of TBAF (1) in THF, we synthesized three new diuorosilicates 4b-4d containing one or two electron donating methoxy groups or one electron withdrawing triuoromethyl group in the aryl rings.We found that TBAT analogues 4b, 4c bearing one or two electron donating groups gave in most cases (2-bromooctane (2a), 2iodooctane (2c), octan-2-mesylate (2b), (1-bromoethyl)benzene (8) and bromocyclopentane (10)) better results in nucleophilic uorination of secondary substrates than TBAF (1) and TBAT (4a), while the presence of the electron withdrawing group led to inferior results.On the other hand, simple TBAF (1) gave better yields of uorination of 2-chlorooctane (2d) and bromocyclohexane (9), indicating probably different mechanism of the uorination/elimination complex.Attempts to improve further uorination selectivity by adding more electron-donating groups failed due to low stability of the corresponding triaryldi-uorosilicates, as was conrmed by 19 F NMR experiments.DFT study of the decomposition of diuorosilicates to uorosilane-uoride complexes disclosed that the activation energy decreases with increased electron density on the modied phenyl group in an order 4-CF 3 C 6 H 4 > C 6 H 5 > 4-MeOC 6 H 4 .and of the project no.21-05926X (measurement of X-ray structures).